Processes for preparing clarithromycin and clarithromycin intermediate, essentially oxime-free clarithromycin, and pharmaceutical composition comprising the same

ABSTRACT

The present invention relates to processes for preparing protected silylated clarithromycin oxime, preferably 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl)oxime (“S-MOP oxime”), and for converting protected silylated clarithromycin oxime, preferably S-MOP oxime, to clarithromycin. Processes for preparing protected silylated clarithromycin oxime according to the present invention, include reacting a silyl oxime derivative with methylating agent in the presence of at least one solvent and a base, where the solvent comprises methyl tertbutyl ether. Processes for converting protected silylated clarithromycin oxime to clarithromycin according to the present invention, include reacting protected silylated clarithromycin oxime with ethanol and water at an ethanol to water ratio of about 1:1, in the presence of an acid and a deoximating agent and cooling the reaction mixture prior to adding sodium hydroxide, where the process takes place without any additional water addition. Further processes for converting protected silylated clarithromycin oxime to clarithromycin, include heating a mixture of protected silylated clarithromycin oxime, acid, and deoximating agent in an ethanol/water solvent to reflux for more than 4 hours, with a two-fold addition of deoximating agent to produce essentially oxime-free clarithromycin.

CROSS REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit of U.S. ProvisionalApplication No. 60/185,888 filed on Feb. 29, 2000, No. 60/189,120 filedon Mar. 14, 2000, and No. 60/213,239 filed on Jun. 22, 2000.

FIELD OF THE INVENTION

[0002] The present invention relates to methods for preparing aprotected silylated clarithromycin oxime, such as6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A9-O-(2-methoxyprop-2-yl)oxime (hereinafter “S-MOP oxime”), which includereacting a silyl oxime derivative with methylating agent while stirringin the presence of at least one solvent, where the solvent includes atleast methyl tert-butyl ether (MTBE), and a base.

[0003] The present invention also relates to a method of converting theprotected silylated clarithromycin oxime to clarithromycin, whichincludes reacting the protected silylated clarithromycin oxime with acidand deoximating agent in the presence of ethanol and water at an ethanolto water ratio of about 1:1. The reaction mixture is cooled to about 20°C. and a base, preferably sodium hydroxide, is added. The method doesnot include any additional water addition to process clarithromycin.

[0004] The present invention further relates to a method of converting aprotected silylated clarithromycin oxime, such as S-MOP oxime, toclarithromycin, which includes heating a mixture of the protectedsilylated clarithromycin oxime, acid, and deoximating agent in anethanol/water solvent to reflux for more than 4 hours, with a two-foldaddition of said deoximating agent. The invention further relates to theessentially oxime-free clarithromycin produced by such a method andpharmaceutical compositions containing the same.

BACKGROUND OF THE INVENTION

[0005] 6-O-methyl erythromycin A (clarithromycin) is a semi syntheticmacrolide antibiotic related to erythromycin A. It exhibits excellentantibacterial activity against gram-positive bacteria, somegram-negative bacteria, anaerobic bacteria, Mycoplasma, and Chlamydia.It is stable under acidic conditions and is efficacious whenadministered orally. Clarithromycin is a useful therapy for infectionsof the upper respiratory tract in children and adults. Clarithromycin isstable under acidic conditions and is efficacious when administeredorally.

[0006] The chemical structure of clarithromycin is:

[0007] Various methods of preparing 6-O-methylerythromycin A fromerythromycin A have been described in the patent literature. One of themost effective methods includes the following steps: 1) protecting the9-oxo group with a substituted oxime group, 2) protecting the hydroxylgroups in positions 2′ and 4″, 3) methylating the hydroxyl in position 6to give a protected sililated clarithromycin oxime, and 4) removing theprotecting groups at the 2′, 4″ and 9 position.

[0008] The third step, which comprises methylating the hydroxyl group atposition 6, is performed in the presence of a solvent. This6-O-methylation of various erythromycin derivatives in convertingerythromycin A to clarithromycin has been reported in several U.S.Patents including U.S. Pat. Nos. 4,680,386 and 4,672,109.

[0009] U.S. Pat. No. 4,680,386 for example, describes a method ofmethylating the hydroxyl group at the 6 position by reacting thecompound with a methylating agent in the presence of a base in anaprotic solvent at a temperature of between 0° C. and room temperature.The '386 patent describes the use of solvents includingN,N-dimethylformamide, dimethyl sulfoxide, hexamethylphosphorictriamide, and a mixture of one or more of these solvents. U.S. Pat. No.4,672,109 describes the use of solvents such as dimethyl sulfoxide,N,N-dimethylformamide, hexamethyl phosphoric triamide, a mixture of twoor more of these solvents or a mixture of one of these solvents andtetrahydrofuran, 1,2-dimethoxyethane and the like. The '109 patentfurther describes a preferred embodiment of this step using a mixture ofdimethyl sulfoxide and tetrahydrofuran. WO 97/19096 describes a mixtureof solvents including N,N-dimethylformamide, dimethyl sulfoxide,N-methyl-2-pyrrolidone, hexamethyl phosphoric triamide, tetrahydrofuran,1,2-dimethoxyethane, acetonitrile and ethyl acetate for use in themethylating step.

[0010] However, several of the above-described solvents are expensive,do not enable selective methylation, produce significant unwanted sideproducts and/or cause complications during later phase separation steps.

[0011] The fourth step includes removing the protecting groups, andthus, converts protected silylated clarithromycin oxime toclarithromycin. Described methods of converting a protected silylatedclarithromycin oxime, such as S-MOP oxime, to clarithromycin includereacting the protected silylated clarithromycin oxime with ethanol inthe presence of an acid and a deoximating agent. The product of thereaction is then washed with water one or more times.

[0012] The ethanol generally also contains water. U.S. Pat. No.4,990,602 has an ethanol to water ratio of 1:4 and does not involvecooling. U.S. Pat. No. 4,670,549 adds sodium hydroxide after cooling atan ethanol to water ratio of 1:3. Neither of these methods lowers theimpurity content of clarithromycin.

SUMMARY OF THE INVENTION

[0013] The present invention relates to methods for preparing aprotected silylated clarithromycin oxime, such as6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A9-O-(2-methoxyprop-2-yl)oxime (“S-MOP oxime”), which include reacting asilyl oxime derivative with methylating agent while stirring in thepresence of at least one solvent and a base, where the solvent includesmethyl tert-butyl ether (MTBE). In the method for preparing theprotected silylated clarithromycin oxime, the methylating agent ispreferably one or more of methyl iodide, methyl bromide,dimethylsulfate, methyl p-toluenesulfonate, or methanesulfonate. Thebase is preferably sodium hydride, potassium hydroxide, or sodiumhydroxide.

[0014] Further embodiments of the present invention relates to methodsof converting a protected silylated clarithromycin oxime, such as S-MOPoxime, to clarithromycin. One such method includes reacting theprotected silylated clarithromycin oxime with acid and a deoximatingagent in the presence of ethanol and water at an ethanol to water ratioof about 1:1. The reaction mixture is cooled to about 20° C. and a base,preferably sodium hydroxide solution, is added. In this method, noadditional water is added to process clarithromycin. Another method ofconverting a protected silylated clarithromycin oxime to clarithromycinincludes heating a mixture of the protected silylated clarithromycinoxime, acid, and deoximating agent in an ethanol/water solvent to refluxfor more than 4 hours, with a two-fold addition of deoximating agent. Inthe latter method, essentially oxime-free clarithromycin is produced,which contains less than 40 ppm of the corresponding oxime intermediate.

DETAILED DESCRIPTION OF THE INVENTION

[0015] Clarithromycin is described, inter alia, in the followingpublications, which are hereby incorporated herein by reference: U.S.Pat. Nos. 3,922,379, 4,331,803, 4,670,549, 4,672,109, 4,680,386,4,808,411, 4,957,905, 4,990,602, 5,837,829, 5,844,105, 5,852,180,5,858,986, 5,919,489, 5,932,710, and 5,945,405.

[0016] The terms “6-O-methylerythromycin A” and “clarithromycin” areused interchangeably herein and are meant to include clarithromycin inany form (such as crystalline Form 0, Form I, Form II or Form IV) orpharmaceutical salts thereof or mixtures thereof, as well as amorphoussolids, syrups, or semisolids comprising clarithromycin in any state ofpurity, unless specified otherwise.

[0017] The present invention relates to increasing the product yield andunwanted side effects produced various steps included in convertingerythromycin A to clarithromycin. Clarithromycin is prepared fromerythromycin A by a variety of synthetic routes. Some of these routesinclude oximation steps and the use of a protected silylatedclarithromycin oxime, such as an S-MOP oxime intermediate.

[0018] The synthetic routes of converting erythromycin A toclarithromycin that are improved herein, are those that utilize aprotected silylated clarithromycin oxime intermediate, such an S-MOPoxime intermediate.

[0019] Synthetic routes of converting erythromycin A to clarithromycininclude methylation of the 6-hydroxy group of erythromycin A. In theconversion process it is necessary to protect various groups, such asthe hydroxy groups at the 2′ and 4″ positions of erythromycin A, whichare potentially reactive with alkylating agents, prior to alkylation ofthe 6-hydroxy group. Examples of methods of preparing clarithromycinusing oxime intermediates are described for example, in U.S. Pat. Nos.4,990,602 and 5,858,986, which each describe a method of preparingclarithromycin from erythromycin A by oximation of the C-9 carbonyl,protection of the C-2′ and C-4″ hydroxy groups, methylation of the C-6hydroxy group, and deoximation and removal of the protecting groups.

[0020] An example of a synthetic route of converting erythromycin A toclarithromycin via oximation, that utilizes a protected silylatedclarithromycin oxime, specifically S-MOP oxime, as an intermediate, isas follows in Scheme 1 (each compound in the process is numbered forease of referencing them herein).

[0021] The present invention is directed to improved methods ofpreparing a protected silylated clarithromycin oxime, preferably anS-MOP oxime (compound 5 in Scheme 1) from a 9-oxim silyl derivative(such as compound 4 in Scheme 1) and of converting a protected silylatedclarithromycin oxime, preferably an S-MOP oxime (compound 7 in Scheme1), to clarithromycin.

[0022] The methods described herein are not limited to use in theprocess shown in Scheme 1. Scheme 1 is provided as a representativescheme in which a protected silylated clarithromycin oxime, such as anS-MOP oxime, is prepared from a silyl derivative and another stepincludes converting the protected silylated clarithromycin oxime toclarithromycin. It would be understood by those in the art that themethods described herein may be used in various schemes for convertingerythromycin A to clarithromycin, which employ a protected silylatedclarithromycin oxime compound as an intermediate therein.

[0023] In the representative process of converting erythromycin A toclarithromycin shown above in Scheme 1, erythromycin A is firstconverted to a protected silylated oxime, such as2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl)oxime(compound 4 in Scheme 1), by methods generally known in the art. Asindicated above, protecting groups protect certain positions frompotentially reacting with alkylating agents during the subsequentmethylation of the 6-hydroxy group, and also protect 3′-dimethylaminogroups from quaternary alkylation.

[0024] Although the conversion from erythromycin A to a protectedsilylated oxime (e.g., 2′,4″-bis(trimethylsilyl)-erythromycin A9-O-(2-methoxyprop-2-yl)oxime) may be accomplished by any methods knownto those in the art, in a preferred method, erythromycin A is firstoximated and subsequently protecting groups are added initially to theoxime group and then to the 2′ and 4″ positions. Suitable methods foroximation and the addition of protecting groups are set forth in U.S.Pat. Nos. 5,858,986 and 4,990,602, which teach general methods ofoximation that may be used in accordance with the present invention,such as by reacting erythromycin A with the substituted hydroxylamineR¹ONH₂, or by reacting erythromycin A with hydroxylamine hydrochloridein the presence of base, or hydroxylamine in the presence of acid,followed by reaction with R¹X, where R¹ is alkoxyalkyl. U.S. Pat. Nos.5,858,986 and 4,990,602 further describe suitable methods for protectingthe oxime group and two hydroxy groups (i.e., at the 2′ and 4″positions) with silyl groups. The hydroxy groups may be protectedsimultaneously or in different steps from one another. Preferred methodsof converting the silyl derivative to a protected silylatedclarithromycin oxime and converting the protected silylatedclarithromycin oxime to clarithromycin are set forth below.

[0025] The step of converting a silyl derivative such as compound 4 to aprotected silylated clarithromycin oxime (such as S-MOP oxime) is amethylation step. In this methylation step, one or more hydroxy groups,such as that at the 6-position, is methylated. One embodiment of thepresent invention relates to methods for preparing a protected silylatedclarithromycin oxime, which includes reacting a silyl oxime derivativewith a methylating agent while stirring in the presence of a solvent anda base.

[0026] The solvent in this embodiment includes MTBE (methyl tertbutylether), preferably along with another aprotic solvent(s). The mostpreferable solvent is a mixture of DMSO (dimethyl sulfoxide) and MTBE.The present inventors have found the MTBE is more selective, cheaper andeasier to recover than solvents described in the literature, includingthe primarily used combination of DMSO with THF (tetrahydrofuran).

[0027] In this embodiment, the silyl derivative is stirred in a solventat about ambient temperature until the silyl derivative is dissolved.For purposes of this specification, ambient temperature is from about20° C. to about 25° C. A further solvent may then be added. The solutionis cooled to a temperature of between about 0° C. and about 20° C.,preferably between about 5 and about 15° C., even more preferably about10° C.

[0028] In this embodiment, a methylating agent is added while stirringthe solution. The methylating agent is preferably an agent such asmethyl iodide, methyl bromide, dimethylsulfate, methylp-toluenesulfonate, methyl methanesulfonate, dimethyl sulfate, and thelike. The methylating agent is most preferably methyl iodide. Although1.0 to 10 molar equivalents of methylating agent can be used per mole ofsilyl derivative, it is sufficient to use between about 1.0 and about3.0 molar equivalents of methylating agent per mole of silyl oximederivative.

[0029] A base is added to the solution of silyl oxime derivative,solvent(s) and methylating agent in this embodiment, and stirred at atemperature-of between about 9° C. and about 25° C., preferably betweenabout 9° C. and about 15° C. until the reaction is essentiallycompleted. The base is preferably one or more of sodium hydride,potassium hydroxide, sodium hydroxide, sodium hydride, potassiumtert-butoxide, potassium hydride, and the like. Most preferably, thebase is powdered potassium hydroxide, which is added to the solution andstirred at about 10° C. The amount of base used is usually from about 1to about 3 molar equivalents of the silyl oxime derivative.

[0030] Preferably the temperature is maintained at about 10° C. to about12° C. while stirring is taking place and the reaction is occurring. Theprogress of the reaction is monitored by HPLC.

[0031] When MTBE is used as a solvent in this embodiment, two phases mayform, making it easier to separate the protected silylatedclarithromycin oxime, than if other solvents are used that form a singlephase. The separation of protected silylated clarithromycin oxime may beperformed by conventional methods. For example, once the reaction iscomplete, the workup of the reaction mixture may include phaseseparation, washing of the MTBE layer with water and evaporation todryness.

[0032] Another embodiment of the present invention relates to convertinga protected silylated clarithromycin oxime, preferably S-MOP oxime,(whether it is arrived at by the method of the above embodiment or byanother method) to clarithromycin, by reacting the protected silylatedclarithromycin oxime with an acid and a deoximating agent in thepresence of aqueous ethanol where the ethanol to water ratio is about1:1. The reaction of the protected silylated clarithromycin oxime withdeoximating agent and acid brings about deoximation together withelimination of the protecting groups. The reaction mixture is thencooled to between about 15° C. and about 25° C., more preferably about20° C., and subsequently a base, preferably sodium hydroxide solution,is added.

[0033] Previously described methods of converting a protected silylatedclarithromycin oxime to clarithromycin include introducing the protectedsilylated clarithromycin oxime into a water/ethanol system in thepresence of an acid and a deoximating agent and refluxing at 80° C.Subsequently, a large amount of water is added. According to thisprocess, the mass ratio between the protected silylated clarithromycinoxime:ethanol:water is about 1:5:5 before the addition of the largeamount of water. The ratio of ethanol to water is about 1:1, beforeadding additional water and about 1:4 after adding additional water.Then, NaOH is added and the solution is cooled to 0° C. This methodresults in the precipitation of clarithromycin. However, this process isdisadvantageous because it doesn't allow purification of the productfrom an impurity, the 11-methyl derivative of clarithromycin. Thisimpurity is referred to as the “dimethyl” form of clarithromycin, whichis difficult to remove. When the ethanol to water ratio is 1:3 or 1:4for example, it is difficult to remove the impurity. If the reactionmixture is not cooled prior to addition of sodium hydroxide, theimpurity content may not decrease.

[0034] The present invention relates to an improved process forobtaining clarithromycin from a protected silylated clarithromycinoxime, such as S-MOP oxime, in which the obtained clarithromycincontains significantly reduced amounts of the “dimethyl” impurity. Themethod includes reacting a protected silylated clarithromycin oxime withan acid (such as formic acid) and a deoximating agent in the presence ofqueous ethanol at an ethanol/water ratio of about 1:1, refluxing thesolution at 80° C., cooling the solution to about 20° C., and addingNaOH.

[0035] In the present method, acid is added to the mixture of protectedsilylated clarithromycin oxime, ethanol, water and deoximating agent andthe mixture is heated at reflux (about 80° C.) Heating is then continuedand the suspension is stirred for an amount of time sufficient to finishthe reaction. The mixture is then cooled to about 20° C. and sodiumhydroxide solution having a concentration of from about 20% to about47%, preferably 47%, is added at this temperature until the pH of thereaction mixture reaches about 10 to about 11, preferably about 10.2 toabout 10.5. Crystalline clarithromycin is then isolated, preferably byfiltration, with no further water addition. The obtained clarithromycinmay subsequently be further purified and/or isolated and the crystallineform of clarithromycin may be altered to the desired form (such ascrystal form 0, I, II, or IV) for use.

[0036] There is need to add no additional water in the method of thepresent invention. Since additional water (that is, water other than thewater present with the ethanol in a ratio of about 1:1 and in sodiumhydroxide solution) is not required in the present method,clarithromycin may be formed with a significant decrease in the amountof impurities.

[0037] The advantages of the present method are inter alia that theclarithromycin produced contains about 50% less of the dimeric impuritythan clarithromycin produced by other processes, and the working volumesare lower. Preferably, the volume ratio of protected silylatedclarithromycin oxime oxime:water:ethanol is about 1:3:3.

[0038] Another embodiment of the present invention also relates toconverting a protected silylated clarithromycin oxime, such as S-MOPoxime, (whether it is arrived at by the method described hereinabove orby another method) to clarithromycin, by heating a mixture of aprotected silylated clarithromycin oxime, acid, and two-fold addition ofdeoximating agent in an ethanol/water solvent to reflux for more than 4hours. Essentially oxime-free clarithromycin, that is clarithromycin,which contains less than 40 ppm of the corresponding oxime intermediate,may be produced by this method.

[0039] As in the previous embodiment, the reaction of protectedsilylated clarithromycin oxime with deoximating agent and acid bringsabout deoximation together with elimination of the protecting groups.The reaction mixture is then cooled to between about 15° C. and about25° C., more preferably about 20° C., and subsequently a base,preferably sodium hydroxide solution, is added.

[0040] Previously described methods of converting a protected silylatedclarithromycin oxime to clarithromycin include introducing the protectedsilylated clarithromycin oxime into a water/ethanol system in thepresence of an acid and a deoximating agent and refluxing for 2 hours inan ethanol/water solvent. The product of this process containsclarithromycin oxime as an impurity.

[0041] By two-fold addition of deoximating agent refluxing for over fourhours, the clarithromycin oxime impurity is largely removed, resultingin relatively pure (essentially oxime-free) clarithromycin. Accordingly,the present invention is also directed to this essentially oxime-freeclarithromycin and pharmaceutical compositions containing theessentially oxime-free clarithromycin. Pharmaceutical compositionscontaining clarithromycin are described for example in U.S. Pat. No.5,858,986.

[0042] In the present method, acid is added to the mixture of S-MOPoxime, ethanol, water and deoximating agent and the mixture is heated atreflux (about 80° C.). Heating is then continued and the suspension isstirred for at least four hours. The mixture is then cooled, preferablyto about 20° C. and sodium hydroxide solution having a concentration offrom about 20% to about 47%, preferably 47%, is added at thistemperature until the pH of the reaction mixture reaches about 10 toabout 11, preferably about 10.2 to about 10.5. Crystallineclarithromycin is then isolated, preferably by filtration, with nofurther water addition. The obtained clarithromycin may subsequently befurther purified and/or isolated and the crystalline form ofclarithromycin may be altered to the desired form (such as crystal form0, I, II, or IV) for use.

[0043] Examples of suitable deoximating agents for use in the methods ofproducing clarithromycin according to the present invention includeinorganic sulfur oxide compounds such as sodium hydrogen sulfite, sodiumpyrosulfate, sodium thiosulfate, sodium sulfite, sodium hydrosulfite,sodium metabisulfite, sodium dithionate, postassium hydrogen sulfite,potassium thiosulfate, potassium metabisulfite and the like. Aparticularly preferred deoximating agent is sodium metabisulfite. Theamount of deoximating agent is about 1 to 10 molar equivalents,preferably 4 to 7 molar equivalents relative to the protected silylatedclarithromycin oxime.

[0044] A non-limiting example of a suitable acid for use in the presentinvention is formic acid. The amount of formic acid added to the mixtureof protected silylated clarithromycin oxime is about 1.5 to 10 molarequivalents, preferably 2 to 5 equivalents relative to the protectedsilylated clarithromycin oxime.

[0045] The following examples are provided to enable one skilled in theart to practice the invention and are merely illustrative of theinvention. The examples should not be read as limiting the scope of theinvention as defined in the claims.

EXAMPLE 1

[0046] This example is directed to a method for preparing a protectedsilylated clarithromycin oxime, particularly the preferred S-MOP oxime,according to the present invention. The example involves reacting asilylated erythromycin A oxime derivative with a methylating agent whilestirring in the presence of at least one solvent and a base.

[0047] MTBE is charged at about ambient temperature (12 liters) and a9-oxime silyl derivative (1 kg) is charged at about ambient temperature,stirring the 9-oxime silyl derivative in the MTBE solvent for severalminutes until the silyl derivative is dissolved and a clear solution isobtained. DMSO (10.0 liters) is added to the clear solution and thesolution is cooled to about 10° C. Methyl iodide (0.218 kg) is added tothe solution while stirring. Powdered potassium hydroxide (0.1 kg) isalso added at 10° C. with stirring.

[0048] Stirring is continued while maintaining the temperature at about10° C. to about 12° C. The progress of the reaction is monitored byHPLC. The reaction is completed after about 60 min. After the reactionis completed it is quenched by adding dimethyl amine solution (40%, 0.6liters) at 10-12° C. and stirring for 30 min. The stirring is thenstopped and the layers are separated. The lower layer is extracted outwith MTBE (4.0 liters). Both MTBE layers, from reaction and fromextraction, are combined and washed with water (5.0 liters). The MTBElayer is distilled under reduced pressure to dryness to receive S-MOPoxime (crude), yield: 1.05 kg. The DMSO layer is taken for recovery.

[0049] Examples 2 and 3 are directed to methods of converting aprotected silylated clarithromycin oxime, particularly the preferredS-MOP oxime, to clarithromycin.

EXAMPLE 2

[0050] S-MOP oxime (20 g) is mixed with aqueous ethanol (120 ml) wherethe water to ethanol ratio is about 1:1 and sodium metabisulfite (13.6g). Formic acid (2.6 g) is added and the mixture is stirred at about 80°C. to the reflux temperature to give clarithromycin. Heating iscontinued and the suspension is stirred for 2 hours. The mixture is thencooled to about 20° C. and sodium hydroxide solution in a concentrationof about 47% is added at about this temperature until the pH reachesabout 10.5. The solid is filtered and dried to give 8.3 g ofclarithromycin, (about 78% based on assay).

EXAMPLE 3

[0051] S-MOP-oxime (20 g) was mixed with aqueous ethanol (120 ml) wherethe water to ethanol ratio is about 1:1 and sodium metabisulfite (13.6g). Formic acid (2.6 g) was added and the mixture was stirred at refluxtemperature for 3-4 hours. The second portion of sodium metabisulfite(13.6 g) was added and the reflux was continued for an additional 34hours. The work up procedure was performed as described in Example 2.The crude clarithromycin was obtained (8.7 g, 82% based on assay) whichafter crystallization from ethanol gives essentially pureclarithromycin, which does not contain any detectable amount ofclarithromycin oxime.

[0052] The present invention provides methods for preparing a protectedsilylated clarithromycin oxime and for converting a protected silylatedclarithromycin oxime to clarithromycin. The invention further providesessentially oxime-free clarithromycin and compositions containingessentially oxime-free clarithromycin. Although the present inventionhas been described with respect to certain exemplary embodiments, suchas those in which the method of preparing a protected silylatedclarithromycin oxime includes reaction in the presence of specificsolvents, bases, or methylating agents, there are many other variationsof the above-described embodiments which will be apparent to thoseskilled in the art, even where elements or steps have not explicitlybeen designated as exemplary. It is understood that these modificationsare within the teaching of the present invention.

We claim:
 1. A method for preparing a protected silylated clarithromycinoxime comprising reacting a silylated erythromycin A oxime derivativewith methylating agent while stirring in the presence of a base and asolvent comprising methyl tertbutyl ether.
 2. The method of claim 1,wherein the methylating agent is selected from the group consisting ofmethyl iodide, methyl bromide, dimethylsulfate, methylp-toluenesulfonate, and methanesulfonate.
 3. The method of claim 1,wherein the base is selected from the group consisting of sodiumhydride, potassium hydroxide, and sodium hydroxide.
 4. The method ofclaim 1, wherein the solvent further comprises dimethyl sulfoxide. 5.The method of claim 1, wherein the protected silylated clarithromycinoxime is 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A9-O-(2-methoxyprop-2-yl)oxime and the silyl oxime derivative is2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl)oxime.6. A method of converting a protected silylated clarithromycin oxime toclarithromycin comprising a) reacting the protected silylatedclarithromycin oxime with acid and deoximating agent in the presence ofethanol and water at an ethanol to water ratio of about 1:1 to obtain asolution, b) refluxing the solution obtained by step a), c) cooling thesolution obtained after step b) to about 15° C. to about 25° C., and d)adding NaOH.
 7. The method of claim 6, wherein the cooling is to about20° C.
 8. The method of claim 6, wherein the acid is formic acid.
 9. Themethod of claim 6, wherein the deoximating agent is sodiummetabisulfite.
 10. The method of claim 6, wherein the protectedsilylated clarithromycin oxime is6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A9-O-(2-methoxyprop-2-yl)oxime.
 11. A method of converting protectedsilylated clarithromycin oxime to clarithromycin including reacting theprotected silylated clarithromycin oxime with acid and deoximating agentin the presence of ethanol and water at an ethanol to water ratio ofabout 1:1 to form a reaction mixture; cooling the reaction mixture toabout 15° C. to about 25° C.; and adding sodium hydroxide solution tothe reaction mixture; wherein essentially no additional water to processclarithromycin.
 12. The method of claim 10 wherein the protectedsilylated clarithromycin oxime is6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime.
 13. The method of claim 11, wherein the cooling is toabout 20° C.
 14. The method of claim 11, wherein the acid is formicacid.
 15. The method of claim 11, wherein the deoximating agent issodium metabisulfite.
 16. Clarithromycin formed by a process comprisingconverting erythromycin A to 2′,4″-bis(trimethylsilyl)-erythromycin A9-O-(2-methoxyprop-2-yl) oxime; reacting2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oximewith methylating agent while stirring in the presence of at least onesolvent and a base, wherein the at least one solvent comprises methyltertbutyl ether, to form6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A9-O-(2-methoxyprop-2-yl) oxime; and reacting the6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A9-O-(2-methoxyprop-2-yl) oxime with an acid and a deoximating agent inthe presence of aqueous ethanol to form clarithromycin.
 17. Theclarithromycin of claim 16, wherein the methylating agent is selectedfrom the group consisting of methyl iodide, methyl bromide,dimethylsulfate, methyl p-toluenesulfonate, and methanesulfonate. 18.The clarithromycin of claim 16, wherein the base is selected from thegroup consisting of sodium hydride, potassium hydroxide, and sodiumhydroxide.
 19. Clarithromycin formed by a process comprising convertingerythromycin A to protected silylated clarithromycin oxime; reacting theprotected silylated clarithromycin oxime with acid and deoximating agentin the presence of ethanol and water at an ethanol to water ratio ofabout 1:1 to form a reaction mixture; cooling the reaction mixture toabout 15° C. to about 25° C.; and adding sodium hydroxide solution tothe reaction mixture.
 20. The method of claim 19, wherein the protectedsilylated clarithromycin oxime is6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime.
 21. The clarithromycin of claim 19, wherein thecooling is to about 20° C.
 22. The clarithromycin of claim 19, whereinthe acid is formic acid.
 23. The clarithromycin of claim 19, wherein thedeoximating agent is sodium metabisulfite.
 24. A method of convertingerythromycin A to clarithromycin comprising converting erythromycin A toprotected silylated clarithromycin oxime; reacting protected silylatedclarithromycin oxime with methylating agent while stirring in thepresence of at least one solvent, wherein the at least one solventcomprises methyl tertbutyl ether, and a base to form 6-O-methylprotected silylated clarithromycin oxime; and reacting the 6-O-methyl-protected silylated clarithromycin oxime with acid and a deoximatingagent in the presence of aqueous ethanol to form clarithromycin.
 25. Amethod of converting erythromycin A to clarithromycin comprisingconverting erythromycin A to protected silylated clarithromycin oxime;and reacting the protected silylated clarithromycin oxime with an acidand deoximating agent in the presence of ethanol and water at an ethanolto water ratio of about 1:1, cooling to about 20° C., and adding sodiumhydroxide solution, wherein essentially no additional water is added toprocess clarithromycin.
 26. The method of claim 25, wherein theprotected silylated clarithromycin oxime is6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime.
 27. A process for preparing essentially oxime-freeclarithromycin, which comprises heating a mixture of protected silylatedclarithromycin oxime, formic acid and a deoximating agent in aethanol/water solvent to reflux for more than 4 hours, with a two-foldaddition of said deoximating agent.
 28. The method of claim 27, whereinthe protected silylated clarithromycin oxime is6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A 9-O-(2-methoxyprop-2-yl) oxime.
 29. Clarithromycin comprising less than 40 ppm of itscorresponding oxime intermediate formed by heating a mixture ofprotected silylated clarithromycin oxime, formic acid and deoximatingagent in an ethanol/water solvent to reflux for more than 4 hours, witha two-fold addition of said deoximating agent.
 30. Clarithromycincomprising less than 40 ppm of its corresponding oxime intermediateformed by a method that includes converting a clarithromycin oximeintermediate to clarithromycin.
 31. Clarithromycin comprising less than40 ppm of its corresponding oxime intermediate formed by a method thatincludes converting 6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A9-O-(2-methoxy prop-2-yl) oxime intermediate to clarithromycin. 32.Clarithromycin comprising less than 40 ppm of its corresponding oximeintermediate formed by heating a mixture of protected silylatedclarithromycin oxime, formic acid and deoximating agent in anethanol/water solvent to reflux for more than 4 hours, with a two-foldaddition of said deoximating agent.
 33. Clarithromycin comprising lessthan 40 ppm of clarithromycin-S-MOP-Oxime intermediate formed by amethod that includes converting a clarithromycin oxime intermediate toclarithromycin.
 34. Clarithromycin comprising less than 40 ppm of itscorresponding oxime intermediate formed by heating a mixture of6-O-methyl-2′,4″-bis(trimethylsilyl)-erythromycin A9-O-(2-methoxyprop-2-yl) oxime, formic acid and deoximating agent in anethanol/water solvent to reflux for more than 4 hours, with a two-foldaddition of said deoximating agent.
 35. A pharmaceutical compositioncomprising the product of claim 29, 30, 31, 32, 33 or 34.